Cell signaling in exercise and sterile inflammation.  

We study cell signaling pathways activated by exercise and sterile inflammation. Extracellular histones are elevated after trauma and have been linked to endotheliopathy. Using intact vascular preparations from mice and human subjects, we found that histones induce large endothelial calcium transients which are paradoxically uncoupled from vasodilation and instead lead to cell death. The results of these studies provide mechanistic insight into the fundamental mechanisms of endothelial injury in sterile inflammation. This  NIH-funded research has provided a critical and necessary basis for the development of novel therapeutic strategies that can protect the endothelium, decrease edema and multi-organ failure, and improve survival after trauma. For example, we identified a small molecule therapeutic which is the subject of a US Patent application (July 2018, UVM Ref. No. C717). Our patent involves a novel mechanism to effectively bind and neutralize cytotoxic circulating histones for treatment of severe acute inflammatory states including trauma.  

  1. Freeman K, Lerman I, Kranias EG, Bohlmeyer T, Bristow MR, Lefkowitz RJ, Iaccarino G, Koch WJ, Leinwand LA. Alterations in cardiac adrenergic signaling and calcium cycling have markedly different effects on the progression of hypertrophic cardiomyopathy, The Journal of Clinical Investigation (2001, 107: 967-974). PMID: 11306600
  2. Lerman I, Harrison B, Freeman K, Hewett TE, Allen DL, Robbins J, Leinwand LA.  Genetic variability in forced and voluntary endurance exercise performance in seven inbred mouse strains, The Journal of Applied Physiology (2002, 92: 2245-2255). PMID: 12015333
  3. Haines L, Villalba N, Sackheim AM, Collier DM, Freeman K. Myogenic tone contributes to the regulation of permeability in mesenteric microvessels. Microvascular Research. 2019 Apr 8. [Epub ahead of print] PMID: 30974113
  4. Collier DM, Villalba N, Sackheim AM, Bonev AD, Miller ZD, Moore JS, Shui B, Lee JC, Lee FK, Reining S, Kotlikoff MI, Nelson MT, Freeman K. Extracellular histones induce calcium signals in the endothelium of resistance-sized mesenteric arteries and cause loss of endothelium-dependent dilation.